SUO 2018: Lithium Treatment Alters Histone Lysine Modification in Prostate Cancers

Phoenix, Arizona ( Lithium is an established treatment for psychiatric conditions, though with known significant side effects. However, in this phase 1 study, the authors assess lithium in men with localized prostate cancer (PCa). Current treatment paradigms for men with localized PCa are surgery or radiation, with no established systemic therapies.

The basis for this study is the groups prior work in cell culture. Specifically, they found that lithium administered to LnCAP cell lines (in vitro and in mice xenografts) inhibit cell proliferation reduced S-phase gene expression mediated by E2F1 transactivation inhibition. As LnCAP is a cell line representing early non-castrate resistant prostate cancer, they sought to evaluate the drug in a similar patient clinical setting. As such, they conducted this study to evaluate the safety and feasibility of Lithium administration in patients with prostate cancer prior to radical prostatectomy. This included a comparison of markers of cell proliferation and transcriptional activation in prostatic tissue after prostatectomy between Lithium and control patients.

Lithium Carbonate was administered to eight patients for four weeks prior to radical prostatectomy using a 3+3 model for dose escalation - doses of 600mg, 900mg, and 1200mg were used. Safety, tolerability, and lithium concentrations in serum and prostate tissue were measured. Immunohistochemical (IHC) analysis of prostatic tissue was conducted to compare expression of molecular markers (Ki-67, H3K4me3, H3K27me3, HeK9Ac and H3K18Ac) between 8 lithium treated and 10 previously collected control prostate samples.

Of the eight patients, five reported adverse effects for a total of twenty events reported over the study period, consistent with patients taking the medication for psychiatric conditions. Eighteen were grade 1 toxicities and two were grade 2 toxicities, but there were no dose limiting toxicities.

Serum lithium levels ranged from 0.1– 1.2MEQ/L. Tissue concentrations in the prostate gland ranged from 1.31 to 9.43 ng/mg (average 3.86 ng/mg) – by dose, they were 1.44ng/mg for the 600mg, 6.09ng/mg for the 900mg, and 4.14ng/mg for the 1200mg group. It is unclear why the tissue concentration did not correlate with dose, but may be patient dependent.
IHC studies showed that Ki-67 index was significantly reduced in lithium-treated prostate cancer specimens (21.1 vs 1.67, p = 0.01). The active transcription histone markers for H3K4 tri-methylation (H3K4me3), and acetylation (H3K9Ac & H3K18Ac) were reduced in lithium-treated prostate cancer. In contrast, the repressive histone modification marker H3K27 trimethylation
(H3K27me3) was increased in prostate cancer specimens.

Figure 1

Based on this phase I study, the authors conclude that lithium was well tolerated and safely administered to patients with prostate cancer undergoing radical prostatectomy – no dose limiting toxicity noted. Lithium serum levels were maintained in a safe range across dose levels.

Lithium concentrated well in the prostate gland with the highest concentration demonstrated in the 900mg dose group. Exploratory IHC analysis also suggested an objective response in cell proliferation and transcriptional modulation.

This has led the team to design a phase 2/3 clinical trial to study the potential therapeutic benefits of lithium in prostate cancer. However, many prior neoadjuvant studies for PCa have failed to demonstrate any significant benefit, so the task ahead is difficult.

Presented By: Derek Jensen, MD

Co-Author(s): Na Yu, PhD; Haixia Xu, MD, PhD; Moben Mirza, MD; Gregory Reed, PhD; Jeffrey Holzbeierlein, MD; Benyi Li, MD, PhD

Institution(s): 1. University of Kansas, Department of Urology; 2. University of Kansas, Department of Clinical Pharmacology

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @TjuUrology, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona